H-Y: Development of a serological assay for H-Y antigen has greatly facilitated study of the H-Y (Histocompatibility-Y) system. We are pursuing two major lines of investigation: (a) We find the same or a cross-reacting H-Y antigen in all vertebrate classes and species so far tested; (in species in which the female is heterogametic (XY) the female rather than the male is H-Y plus). Such evolutionary conservation of H-Y structure implies a vital function. Our hypothesis is that H-Y is the determinant of primary sex. Our plans include more extensive study of the phylogenetic representation of H-Y, especially for the light this may throw on the vexed question of primary sex determination. (b) Because we have so far found no exception to the rule that in XY-male species the H-Y plus phenotype is invariably and exclusively associated with at least rudimentary testicular development, H-Y typing offers entirely new opportunities for the study and diagnosis of aberrations of sexual development in man. Our plans include continued investigation of such clinical material. Sk: The implications of the Sk system(s) are both practical and theoretical: (a) There is now no question that they provide a basis for tissue-selective homograft rejections. (b) 1. They provide further valuable data on the operation of selective expression of the genome in composing the structure of cell surfaces. We now have strong evidence for the existence of at least two genetically unlinked Sk systems in mice. (b) 2. Sk systems can be used to provide indisputable evidence that self-reactive clones of immunocompetent cells exist within the adult immune system. Our plans include experiments designed to settle conclusively the question whether Sk-determined rejection by chimeras is in fact mediated by a donor cell population that has lost self-tolerance through residence in an antigen-free environment, and other experiments to determine whether self-tolerance is maintained in the normal mouse by circulating Sk antigen.